Abstract
Background
Although the function of hypoxia-inducible factor 1 (HIF1) in many kinds of solid tumor has been revealed, the significance of HIF1 in osteosarcoma is still controversial and not well understood.
Methods
Immunohistochemistry was used to detect HIF1 expression. The correlation between HIF1 and clinicopathology factors was analyzed by use of chi-squared tests. The prognostic value of HIF1 was evaluated by univariate and multivariate analysis. Moreover, the function of HIF1 in osteosarcoma cells was further investigated in in-vitro experiments by regulating HIF1 and vascular endothelial growth factor-A (VEGF-A) expression.
Results
Expression of HIF1 was high for 56.82 % of the samples in our investigation. HIF1 expression was significantly associated with positive metastasis (P = 0.037). By use of the Kaplan–Meier method, high expression of HIF1 was proved to be related to poorer overall survival (P = 0.007). By use of a Cox-regression model, HIF1 was identified as an independent prognostic biomarker (P = 0.019). We also proved that HIF1 can promote osteosarcoma invasion in hypoxia by inducing VEGF-A expression.
Conclusions
HIF1 was identified as an independent prognostic biomarker in osteosarcoma. It can promote osteosarcoma cell invasion by inducing VEGF-A expression, indicating that HIF1 is a potential drug target in osteosarcoma.
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References
Luetke A, Meyers PA, Lewis I et al (2014) Osteosarcoma treatment—where do we stand? A state of the art review. Cancer Treat Rev 40:523–532
Ottaviani G, Jaffe N (2009) The epidemiology of osteosarcoma. Cancer Treat Res 152:3–13
Bielack S, Carrle D, Casali PG (2009) Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20(Suppl 4):137–139
Moore DD, Luu HH (2014) Osteosarcoma. Cancer Treat Res 162:65–92
Guijarro MV, Ghivizzani SC, Gibbs CP (2014) Animal models in osteosarcoma. Front Oncol 4:189
Yao Y, Dong Y, Lin F et al (2009) The expression of CRM1 is associated with prognosis in human osteosarcoma. Oncol Rep 21:229–235
Jaffe N (2009) Adjuvant chemotherapy in osteosarcoma: an odyssey of rejection and vindication. Cancer Treat Res 152:219–237
Baumhoer D, Smida J, Zillmer S et al (2012) Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma. Mod Pathol 25:522–528
Szuhai K, Cleton-Jansen AM, Hogendoorn PC et al (2012) Molecular pathology and its diagnostic use in bone tumors. Cancer Genet 205:193–204
Zeng W, Wan R, Zheng Y et al (2011) Hypoxia, stem cells and bone tumor. Cancer Lett 313:129–136
Schofield CJ, Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5:343–354
Brahimi-Horn MC, Pouyssegur J (2009) HIF at a glance. J Cell Sci 122:1055–1057
Ivan M, Kondo K, Yang H et al (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for o2 sensing. Science 292:464–468
Jiang BH, Semenza GL, Bauer C et al (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of o2 tension. Am J Physiol 271:C1172–C1180
Iyer NV, Kotch LE, Agani F et al (1998) Cellular and developmental control of o2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12:149–162
Loor G, Schumacker PT (2008) Role of hypoxia-inducible factor in cell survival during myocardial ischemia-reperfusion. Cell Death Differ 15:686–690
Kappler M, Taubert H, Eckert AW (2011) Oxygen sensing, homeostasis, and disease. N Engl J Med 365:1845–1846 (author reply 1846)
Semenza GL (2014) Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Ann Rev Pathol 9:47–71
Shan B, Gerez J, Haedo M et al (2012) RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells. Endocr Relat Cancer 19:13–27
Enneking WF (1986) A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res 9–24
Xia LM, Huang WJ, Wang B et al (2009) Transcriptional up-regulation of FoxM1 in response to hypoxia is mediated by HIF-1. J Cell Biochem 106:247–256
Elbashir SM, Harborth J, Lendeckel W et al (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498
Sowter HM, Raval RR, Moore JW et al (2003) Predominant role of hypoxia-inducible transcription factor (hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 63:6130–6134
Takei Y, Kadomatsu K, Yuzawa Y et al (2004) A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics. Cancer Res 64:3365–3370
Kappler M, Rot S, Taubert H et al (2007) The effects of knockdown of wild-type survivin, survivin-2b or survivin-delta3 on the radiosensitization in a soft tissue sarcoma cells in vitro under different oxygen conditions. Cancer Gene Ther 14:994–1001
Feige E, Yokoyama S, Levy C et al (2011) Hypoxia-induced transcriptional repression of the melanoma-associated oncogene MITF. Proc Natl Acad Sci USA 108:E924–E933
Busca R, Berra E, Gaggioli C et al (2005) Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (mitf) in melanoma cells. J Cell Biol 170:49–59
Zelzer E, Mamluk R, Ferrara N et al (2004) VEGFA is necessary for chondrocyte survival during bone development. Development 131:2161–2171
Weijts BG, Bakker WJ, Cornelissen PW et al (2012) E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J 31:3871–3884
Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732
Dang CV, Semenza GL (1999) Oncogenic alterations of metabolism. Trends Biochem Sci 24:68–72
Yang QC, Zeng BF, Dong Y et al (2007) Overexpression of hypoxia-inducible factor-1alpha in human osteosarcoma: correlation with clinicopathological parameters and survival outcome. Jpn J Clin Oncol 37:127–134
Mizobuchi H, Garcia-Castellano JM, Philip S et al (2008) Hypoxia markers in human osteosarcoma: an exploratory study. Clin Orthop Relat Res 466:2052–2059
Mayes PA, Campbell L, Ricci MS et al (2005) Modulation of trail-induced tumor cell apoptosis in a hypoxic environment. Cancer Biol Ther 4:1068–1074
Mathupala SP, Rempel A, Pedersen PL (2001) Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 276:43407–43412
Kilic M, Kasperczyk H, Fulda S et al (2007) Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. Oncogene 26:2027–2038
Bhattacharya S, Michels CL, Leung MK et al (1999) Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 13:64–75
Masson N, Willam C, Maxwell PH et al (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20:5197–5206
Nardinocchi L, Puca R, Guidolin D et al (2009) Transcriptional regulation of hypoxia-inducible factor 1alpha by hipk2 suggests a novel mechanism to restrain tumor growth. Biochim Biophys Acta 1793:368–377
Yee KM, Spivak-Kroizman TR, Powis G (2008) Hif-1 regulation: not so easy come, easy go. Trends Biochem Sci 33:526–534
Bae SH, Jeong JW, Park JA et al (2004) Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem Biophys Res Commun 324:394–400
Loboda A, Jozkowicz A, Dulak J (2010) HIF-1 and HIF-2 transcription factors—similar but not identical. Mol Cells 29:435–442
Giaccia A, Siim BG, Johnson RS (2003) HIF-1 as a target for drug development. Nat Rev Drug Discov 2:803–811
Chau NM, Rogers P, Aherne W et al (2005) Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. Cancer Res 65:4918–4928
Yonekura S, Itoh M, Okuhashi Y et al (2013) Effects of the HIF1 inhibitor, echinomycin, on growth and notch signalling in leukaemia cells. Anticancer Res 33:3099–3103
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Zhao, H., Wu, Y., Chen, Y. et al. Clinical significance of hypoxia-inducible factor 1 and VEGF-A in osteosarcoma. Int J Clin Oncol 20, 1233–1243 (2015). https://doi.org/10.1007/s10147-015-0848-x
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DOI: https://doi.org/10.1007/s10147-015-0848-x